Herbal formulations

ABSTRACT

A formulation comprising a variety of Chinese herbs is disclosed for the treatment of cancer and side effects associated with the treatment of cancer.

FIELD OF THE INVENTION

This invention generally relates to herbal formulations and uses thereofin improving the well being of a subject, and which may additionally beused in e.g., adjuvant therapy for patients suffering from a variety ofdisorders, e.g., cancer.

BACKGROUND OF THE INVENTION

Medicinal herbs have been traditionally used for a variety of purposes,particularly to prevent and treat a variety of diseases includingcancer. Some of the most important chemotherapeutic agents used in thetreatment of breast cancer are derivatives of herbal remedies. Theseinclude the taxanes obtained from the Pacific yew tree, Taxus brevifoliareserpine, and vincristine and vinblastine which are obtained from theRosy periwinkle shrub. The use of botanical medicine is widespread inall regions of the developing world and is rapidly growing inindustrialized countries especially among patients diagnosed withlife-threatening diseases such as cancer.

Despite their broad use, there exists insufficient scientific data onthe safety and efficacy of many of the herbal therapies. Recently, alarge in vitro study on the effect of more than 70 Chinese herbsextracts on growth of five breast cancer cell lines found that 21% ofthe herbal extracts demonstrated more than 50% growth inhibition on atleast 4 from the 5 cell lines [1].

The emphasis of the Chinese medicine is on the treatment of the body asa whole. Chinese medicine views include a three-fold approach of usingherbs that treat (I) the vitality (tonifying herbs), (II) the cancer(anti-cancer herbs) and (III) the side effects of chemotherapy.

In the Materia Medica of Chinese medicine [2], these herbs are selectedfrom 8 classic categories (which are used traditionally to categorizeChinese herbs): (1) herbs that tonify the Qi; (2) herbs that tonifyBlood; (3) herbs that clear heat and relieve toxicity; (4) herbs thatclear heat and fire; (5) herbs that regulate the flow of Qi; (6) herbsthat drain “dampness”; (7) herbs that invigorate the blood; and (8)herbs that tonify the Yin.

REFERENCES

-   [1] Campbell M J, Hamilton B, Shoemaker M, Tagliaferri M, Cohen I,    Tripathy D Antiproliferative activity of Chinese medicinal herbs on    breast cancer cells in vitro Anticancer Res. 2002 November-December;    22(6C):3843-52.-   [2] Bensky Dan and Gamble Andrew Chinese Herbal Medicine: Materia    Medica Eastland press, Seattle, Wash. 98111, USA.

SUMMARY OF THE INVENTION

The inventors of the present invention have now designed andsuccessfully practiced unique formulations comprising a combination ofherbs. The formulations were tested in vitro as well as in vivo on humansubjects and were found to substantially improve the well-being of asubject suffering from a life-threatening disease or disorder or from acondition which is associated therewith. In particular, the formulationsof the invention have been found effective in ameliorating multiple sideeffects associated with chemotherapy and in imposing anti-proliferativeeffect on the cancer cells.

Thus, in one aspect of the present invention there is provided a herbalformulation comprising a combination of at least four herbs, each beingselected from:

at least one herb that tonifies the Qi;

at least one herb that drains dampness;

at least one herb that tonifies blood;

at least one herb that invigorates the blood;

at least one herb that regulates the flow of Qi;

at least one herb that tonifies yin;

at least one herb that clears heat and relieves toxicity; and

at least one herb that clears heat and fire.

Each herb may be in a solid or liquid form or in a solution form, namelydissolved in a solid or liquid carrier.

For purposes of clarity, it should be noted that a formulation accordingto the invention comprises at least 4 herbs, each being selected from adifferent category of the categories listed above. The formulation maycomprise more than 4 herbs; however, at least 4 of which are ofdifferent categories. For example, one formulation according to theinvention may comprise one herb that tonifies the Qi, one herb thatdrains dampness, one herb that tonifies blood and one herb thatinvigorates the blood. A second formulation may comprise a combinationof 5 herbs as follows: two herbs that tonify the Qi, one herb thatdrains dampness, one herb that tonifies blood and one herb thatinvigorates the blood. A different formulation comprising a combinationof 5 herbs may comprise one herb that tonifies the Qi, one herb thatdrains dampness, one herb that tonifies blood, one herb that clears heatand fire and one herb that invigorates the blood. Thus, any suchcombination is within the scope of the present invention, even if notmentioned per se.

Additionally, it should be noted that in the specification providedbelow, for each herbal component of a formulation of the invention, twonames are provided for each herb: a Latin name and a Chinese name. Inthe terminology used herein, the Latin name is given first, followed bythe Chinese name which is typically given in parenthesis. For example,for the herb referred to as “Astragalus Membranaceus (Huang Qi)”,Astragalus Membranaceus is the Latin name and Huang Qi is its Chinesename.

As used herein the term “tonifies the Qi” refers to a herb (or a herbalcomponent) that strengthens the vitality and enhances the immune systemand that has a general tonic effect and strengthening weakness. The atleast one herb that tonifies the Qi is thus selected from AstragalusMembranaceus (Huang Qi), Atractylodes Macrocephala (Bai zhu), GinsengRadix (Ren Shen), Radix Codonopsitis Pilosulae (Dang Shen),Pseudostellaiae Heterophillae (Tai Zi Shen) and Redix GlycyrrhizaeUralensis (Gan Cao).

The term “drains dampness” refers to a herb (or a herbal component) ofthe formulation which effects the fluid production in the body, inparticular the pathogenic formation of fluids such as phlegm, edema, andany fluid associated swelling. The term also refers to a herb which hasa diuretic effect. The at least one herb that drains dampness isselected from Poriae Cocos (Fu Ling), Coicis Lachryma-jobi Semen (Yi YiRen), Herba Lobeliae Chinensis Cum Radice (Ban Bian Lian), SemenPlantaginis (Che Qian Zi), Fructus Kochia Scopariae (Di Fu Zi) andRhizoma Alismatis (Ze Xie).

The term “tonifies blood” refers to a herb (or a herbal component) whichenhances the formation of blood. The at least one herb that tonifiesblood is selected from Lycium Chinense (Gou Qi Zi), Radix PaeoniaeLactiflorae (Bai Shao), Radix Angelica Sinensis (Dang Gui), ArilusEuphoriae Longanae (Long Yang Rao), Mori Albae Fructus (Sang Shen),Rhemanniae Glutinosae Conquitae Radix (Shu Di Huang) and Radix Polygonummultiflorum (He Shou wu).

The term “invigorates the blood” refers to a herb (or a herbalcomponent) which effects movement, fluidity and/or coagulation of blood.The at least one herb that invigorates the blood is selected fromPaeonia Obovata (Chi Shao), Radix Salviae Miltiorrhizae (Dan Shen),Radix Ligustici Chuanxiong (Chuanxiong), Flos Carthami Tinctorii (HomgHua), Radix Et Caulis Jixueteng (Ji Xue Tang), Curcumae, Tuber (Yu Jin),Persicae, Semen (Tao Ren) and Curcuma Zedoaria (E-Zhu).

The term “regulates the flow of Qi” refers to a herb (or a herbalcomponent) which regulates the malfunction and obstruction and, inparticular, gastrointestinal dysfunction which causes pain ormalabsorption. The at least one herb that regulates the flow of Qi isselected from Citrus Reticulata (Chen Pi), Aucklandiae Lappae Radix (MuXiang), Diospyri Kaki Calyx (Xi Di), Cyperi Rotundi Rhizoma (Xiang Fu),Citri Aurantii Fructus (Zhi Ke) and Citri Aurantii Fructus Immaturus(Zhi Shi).

The term “tonifies yin” refers to a herb (or a herbal component) whichenhances bodily function by strengthening, nourishing and moistening,i.e., by providing the nourishment required for cellular growth and byincreasing the production of physiological fluids when there is dryness.The at least one herb that tonifies the yin is selected from LigustrumLucidum (Niu Zhen Zhi), Ophiopogon Japonicus (Mai men Dong), GlehniaLittoralis (Bei Sha Shen), Sangjisheng, Ramulus (Sang Zi Sheng),Plastrum, Testudinis (Gui Ban), Ophiopogonis Japonici, Tuber (MaimenDong), Panacis Quinquefolii, Radix (Xi Yang Shen) and Radix AdenophoraeSeu Glehniae (Sha Shen).

The term “clears heat and relieves toxicity” refers to a herb (or aherbal component) which treats fever and infections including purulentinfections and abscesses and which has at least one of the effectsselected from an antiviral effect, an antibacterial effect, ananti-inflammatory effect and anti-infectious effect. The at least oneherb that clears heat and relieves toxicity is selected from OldenlandiaDiffusa (Bai Hua She She cao), Scutellaria Barbata (Ban Zhi Lian), RadixIsatidis Seu Baphicacanthi (Ban Lan Gen), Flos Lonicerae Japonicae (JinYin Hua), Taraxaci Mongolici Cum Radice Herba (Pu Gong Yin), SophoraeSubprostratae Radix (Shan Dou Gen), Smilacis Glabrae, Rhizoma (Tu FuLing) and Pseudobulbus Shancigu (Shan Ci Gu).

The term “clears heat and fire” refers to a herb (or a herbal component)which treats high fever and side effects thereof such as irritability,thirst, delirium or any other side effect associated with high fever asknown in the art. The at least one herb that clears heat and fire isselected from Prunella Vulgaris (Xia Ku Cao), Rhizoma, PhragmitisCommunis (Lu Gen), Gardeniae Jasminoidis Fructus (Zhi Zi), AnemarrhenaeAsphodeloidis Rhizoma (Zi Mu), Nelumbinis Nuciferae Semen (Lian Xin) andHerba Lophatheri Gracilis (Dan Zhu Ye).

In some embodiments, the herbal formulation comprises a combination ofherbs, at least one herb of each of said categories.

In some embodiments, the herbal formulation comprises at least one herbthat tonifies the Qi, at least one herb that tonifies blood, at leastone herb that clears heat and fire and at least one herb that clearsheat and relieves toxicity.

In some other embodiments, the herbal formulation comprises two herbsthat tonify the Qi, three herbs that tonify blood, three herbs thattonify yin, two herbs that clear heat and relieve toxicity, one herbthat clears heat and fire, one herb that regulates the flow of Qi, oneherb that drains dampness and one herb that invigorates the blood.

In some embodiments, the herbs that tonify the Qi are AstragalusMembranaceus (Huang Qi) and/or Atractylodes Macrocephala (Bai zhu); theherbs that tonify blood are Lycium Chinense (Gou Qi Zi) and/or PaeoniaLactiflora (Bai Shao) and/or Milletia Reticulata (Ji Xue Teng); theherbs that tonify yin are Ligustrum Lucidum (Niu Zhen Zhi) and/orOphiopogon Japonicus (Mai men Dong) and/or Glehnia Littoralis (Bei ShaShen); the herbs that clear heat and relieve toxicity are OldenlandiaDiffusa (Bai Hua She She cao) and/or Scutellaria Barbata (Ban Zhi Lian);the herb that clears heat and fire may be Prunella Vulgaris (Xia KuCao); the herb that regulates the flow of Qi may be Citrus Reticulata(Chen Pi); the herb that drains dampness may be Poriae Cocos (Fu Ling);and the herb that invigorates the blood may be Paeonia Obovata (ChiShao).

In further embodiments, the herbs that tonify the Qi are AstragalusMembranaceus (Huang Qi) and Atractylodes Macrocephala (Bai zhu); theherbs that tonify blood are Lycium Chinense (Gou Qi Zi), PaeoniaLactiflora (Bai Shao) and Milletia Reticulata (Ji Xue Teng); the herbsthat tonify yin are Ligustrum Lucidum (Niu Zhen Zhi), OphiopogonJaponicus (Mai men Dong) and Glehnia Littoralis (Bei Sha Shen); theherbs that clear heat and relieve toxicity are Oldenlandia Diffusa (BaiHua She She cao) and Scutellaria Barbata (Ban Zhi Lian); the herb thatclears heat and fire is Prunella Vulgaris (Xia Ku Cao); the herb thatregulates the flow of Qi is Citrus Reticulata (Chen Pi); the herb thatdrains dampness is Poriae Cocos (Fu Ling); and the herb that invigoratesthe blood is Paeonia Obovata (Chi Shao).

In further embodiments, a formulation according to the inventioncomprises Astragalus Membranaceus (Huang Qi), Poriae Cocos (Fu Ling),Atractylodes Macrocephala (Bai zhu), Lycium Chinense (Gou Qi Zi),Ligustrum Lucidum (Niu Zhen Zhi), Paeonia Lactiflora (Bai Shao), PaeoniaObovata (Chi Shao), Citrus Reticulata (Chen Pi), Ophiopogon Japonicus(Mai men Dong), Milletia Reticulata (Ji Xue Teng), Oldenlandia Diffusa(Bai Hua She She cao), Scutellaria Barbata (Ban Zhi Lian), PrunellaVulgaris (Xia Ku Cao) and Glehnia Littoralis (Bei Sha Shen).

In some embodiments, the formulation comprises between about 1-30%Astragalus Membranaceus (Huang Qi), between about 1-20% Poriae Cocos (FuLing), between about 1-20% Atractylodes Macrocephala (Bai zhu), betweenabout 1-30% Lycium Chinense (Gou Qi Zi), between about 1-30% LigustrumLucidum (Niu Zhen Zhi), between about 1-30% Paeonia Lactiflora (BaiShao), between about 1-20% Paeonia Obovata (Chi Shao), between about1-20% Citrus Reticulata (Chen Pi), between about 1-30% OphiopogonJaponicus (Mai men Dong), between about 1-30% Milletia Reticulata (JiXue Teng), between about 1-45% Oldenlandia Diffusa (Bai Hua She Shecao), between about 1-45% Scutellaria Barbata (Ban Zhi Lian), betweenabout 1-45% Prunella Vulgaris (Xia Ku Cao) and between about 1-30%Glehnia Littoralis (Bei Sha Shen).

In further embodiments, the formulation comprises between about 5-20%Astragalus Membranaceus (Huang Qi), between about 2-10% Poriae Cocos (FuLing), between about 2-10% Atractylodes Macrocephala (Bai zhu), betweenabout 3-15% Lycium Chinense (Gou Qi Zi), between about 5-30% LigustrumLucidum (Niu Zhen Zhi), between about 4-30% Paeonia Lactiflora (BaiShao), between about 2-19% Paeonia Obovata (Chi Shao), between about1-10% Citrus Reticulata (Chen Pi), between about 2-10% OphiopogonJaponicus (Mai men Dong), between about 5-12% Milletia Reticulata (JiXue Teng), between about 7-45% Oldenlandia Diffusa (Bai Hua She Shecao), between about 5-28% Scutellaria Barbata (Ban Zhi Lian), betweenabout 5-35% Prunella Vulgaris (Xia Ku Cao) and between about 5-20%Glehnia Littoralis (Bei Sha Shen).

In further embodiments, the formulation comprises between about 5-10%Astragalus Membranaceus (Huang Qi), between about 2-10% Poriae Cocos (FuLing), between about 3-10% Atractylodes Macrocephala (Bai zhu), betweenabout 5-10% Lycium Chinense (Gou Qi Zi), between about 5-15% LigustrumLucidum (Niu Zhen Zhi), between about 4-12% Paeonia Lactiflora (BaiShao), between about 2-10% Paeonia Obovata (CM Shao), between about 1-8%Citrus Reticulata (Chen Pi), between about 2-8% Ophiopogon Japonicus(Mai men Dong), between about 5-10% Milletia Reticulata (Ji Xue Teng),between about 7-20% Oldenlandia Diffusa (Bai Hua She She cao), betweenabout 5-15% Scutellaria Barbata (Ban Zhi Lian), between about 5-15%Prunella Vulgaris (Xia Ku Cao) and between about 5-15% GlehniaLittoralis (Bei Sha Shen).

In some embodiments, the formulation comprises about 8.1% AstragalusMembranaceus (Huang Qi), about 4.9% Poriae Cocos (Fu Ling), about 4.9%Atractylodes Macrocephala (Bai zhu), about 6.5% Lycium Chinense (Gou QiZi), about 8.1% Ligustrum Lucidum (Niu Zhen Zhi), about 6.5% PaeoniaLactiflora (Bai Shao), about 4.9% Paeonia Obovata (Chi Shao), about 4.9%Citrus Reticulata (Chen Pi), about 6.5% Ophiopogon Japonicus (Mai menDong), about 8.1% Milletia Reticulata (Ji Xue Teng), about 12.2%Oldenlandia Diffusa (Bai Hua She She cao), about 9.8% ScutellariaBarbata (Ban Zhi Lian), about 8.1% Prunella Vulgaris (Xia Ku Cao) andabout 6.5% Glehnia Littoralis (Bei Sha Shen).

In some embodiments, the herbal formulation further comprises at leastone further herb selected from Cordyceps Sinensis (dong chong xia cao),Schizandra Chinensis (Wu Wei Zi), Commiphora Molmol (Mo Yao),Anemarrhena asphodeloides (Zhi mu), Pseudostellariae Heterophyllae (TaiZhi Shen), Radix Glycyrrhizae (Gan Cao), Massa Fermentata (Shen Qu),Fructus Hordei Germinatus (Mai Ya) and Gigeriae galli Endotheliumcorneum (Ji Nei Jin).

In further embodiments, the at least one further herb is added in anamount ranging between about 1 and 30% of the total weight of the herbalformulation. In some embodiments, Cordyceps Sinensis (Dong Chong XiaCao) may be present in the formulation in an amount between about 1 and30%, Schizandra Chinensis (Wu Wei Zi) in an amount between about 1 and20%, Commiphora Molmol (Mo Yao) in an amount between about 1 and 20%,Anemarrhena asphodeloides (Zhi Mu) in an amount between about 1 and 20%,Pseudostellariae Heterophyllae (Tai Zhi Shen) in an amount between 1 and30%, Radix Glycyrrhizae (Gan Cao) in an amount between about 1 and 20%,Massa Fermentata (Shen Qu) in an amount between about 1 and 20%, FructusHordei Germinatus (Mai Ya) in an amount between about 1 and 10% andGigeriae galli Endothelium corneum (Ji Nei Jin) in an amount between 1and 10% of the total weight (wt %) of the formulation.

In some embodiments, the formulation may further comprise at least oneadditional herb that tonifies the Qi, said herb being selected fromGinseng Radix (Ren Shen), Rhizoma Atractylodis Macrocephalae (Bai Zhu),Radix Codonopsitis Pilosulae (Dang Shen), Ganoderma Lucidum (Reishi),Pseudostellaiae Heterophillae Radix (Tai Zi Shen) and Redix GlycyrrhizaeUralensis (Gan Cao).

In some embodiments, the at least one additional herb that tonifies theQi is present in the formulation in the following amounts: about 1-30%Ginseng Radix (Ren Shen), about 1-30% Rhizoma Atractylodis Macrocephalae(Bai Zhu), about 1-30% Radix Codonopsitis Pilosulae (Dang Shen), about1-20% Ganoderma Lucidum (Reishi), about 1-20% PseudostellaiaeHeterophillae Radix (Tai Zi Shen) and about 1-20% Redix GlycyrrhizaeUralensis (Gan Cao).

In some embodiments, the formulation further comprises at least one herbthat drains dampness, said herb being selected from Coicis Lachryma-jobiSemen (Yi Yi Ren), Herba Lobeliae Chinensis Cum Radice (Ban Bian Lian),Semen Plantaginis (Che Qian Zi), Fructus Kochia Scopariae (Di Fu Zi) andAlismatis Orientalis, Rhizoma (Ze Xie).

In some embodiments, the at least one additional herb that drainsdampness is present in the formulation in the following amounts: about1-30% Coicis Lachryma-jobi Semen (Yi Yi Ren), about 1-20% Herba LobeliaeChinensis Cum Radice (Ban Bian Lian), about 1-20% Semen Plantaginis (CheQian Zi), about 1-20% Fructus Kochia Scopariae (Di Fu Zi) and about1-20% Alismatis Orientalis, Rhizoma (Ze Xie).

In some embodiments, the formulation further comprises at least oneadditional herb that tonifies blood, said herb being selected from RadixPaeoniae Lactiflorae (Bai Shao), Radix Angelica Sinensis (Dang Gui),Arilus Euphoriae Longanae (Long Yang Rao), Mori Albae Fructus (SangShen) and Rhemanniae Glutinosae Conquitae Radix (Shu Di Huang).

In some embodiments, the at least one herb that tonifies blood ispresent in the formulation in the following amounts: about 1-30% RadixPaeoniae Lactiflorae (Bai Shao), about 1-30% Radix Angelica Sinensis(Dang Gui), about 1-30% Arilus Euphoriae Longanae (Long Yang Rao), about1-30% Mori Albae Fructus (Sang Shen) and about 1-30% RhemanniaeGlutinosae Conquitae Radix (Shu Di Huang).

In some embodiments, the formulation further comprises at least oneadditional herb that tonifies the yin, said herb being selected fromSangjisheng, Ramulus (Sang Zi Sheng), Plastrum, Testudinis (Gui Ban),Ophiopogonis Japonici, Tuber (Mai Men Dong), Panacis Quinquefolii, Radix(Xi Yang Shen) and Adenophorae Seu Glehniae and Radix (Sha Shen).

In some embodiments, the at least one additional herb that tonifies theyin is present in the formulation in the following amounts: about 1-30%Sangjisheng, Ramulus (Sang Zi Sheng), about 1-30% Plastrum Testudinis(Gui Ban), about 1-30% Ophiopogonis Japonici Tuber (Mai Men Dong), about1-30% Panacis Quinquefolii Radix (Xi Yang Shen) and about 1-30%Adenophorae Seu Glehniae Radix (Sha Shen).

In some embodiments, the formulation further comprises at least oneadditional herb that invigorates blood, said herb being selected fromRadix Salviae Miltiorrhizae (Dan Shen), Radix Ligustici Chuanxiong, FlosCarthami Tinctorii (Homg Hua), Radix Et Caulis Jixueteng (Ji Xue Tang),Curcumae Tuber (Yu Jin), Persicae Semen (Tao Ren) and Curcuma Zedoaria(E-Zhu).

In some embodiments, the at least one additional herb that invigoratesblood is present in the formulation in the following amounts: about1-30% Radix Salviae Miltiorrhizae (Dan Shen), about 1-30% RadixLigustici Chuanxiong (Chuanxiong), about 1-30% Flos Carthami Tinctorii(Homg Hua), about 1-30% Radix Et Caulis Jixueteng (Ji Xue Tang), about1-30% Curcumae Tuber (Yu Jin), about 1-30% Persicae Semen (Tao Ren) andabout 1-30% Curcuma Zedoaria (E-Zhu).

In some embodiments, the formulation further comprises at least oneadditional herb that regulates the flow of Qi, said herb being selectedfrom Aucklandiae Lappae Radix (Mu Xiang), Diospyri Kaki Calyx (Shi Di),Cyperi Rotundi Rhizoma (Xiang Fu), Citri Aurantii Fructus (Zhi Ke) andCitri Aurantii Fructus Immaturus (Zhi Shi).

In some embodiments, the at least one additional herb that regulates theflow of Qi is present in the formulation in the following amounts: about1-20% Aucklandiae Lappae Radix (Mu Xiang), about 1-20% Diospyri KakiCalyx (Shi DI), about 1-20% Cyperi Rotundi Rhizoma (Xiang Fu), about1-20% Citri Aurantii Fructus (Zhi Ke) and about 1-20% Citri AurantiiFructus Immaturus (Zhi Shi).

In some embodiments, the formulation further comprises at least oneadditional herb that clears heat and relieves toxicity, said herb beingselected from Radix Isatidis Seu Baphicacanthi (Ban Lan Gen), HerbaScutellariae Barbatae (Ban Zhi Lian), Flos Lonicerae Japonicae (Jin YinHua), Taraxaci Mongolici Cum Radice Herba (Pu Gong Yin), SophoraeSubprostratae Radix (Shan Dou Gen), Smilacis Glabrae, Rhizoma (Tu FuLing) and Pseudobulbus Shancigu (Shan Ci Gu).

In some embodiments, the at least one herb that clears heat and relievestoxicity is present in the formulation in the following amounts: about1-45% of Radix Isatidis Seu Baphicacanthi (Ban Lan Gen), about 1-45%Herba Scutellariae Barbatae (Ban Zhi Lian), about 1-45% Flos LoniceraeJaponicae (Jin Yin Hua), about 1-45% Taraxaci Mongolici Cum Radice Herba(Pu Gong Yin), about 1-45% Sophorae Subprostratae Radix (Shan Dou Gen),about 1-45% Smilacis Glabrae, Rhizoma (Tu Fu Ling) and about 1-45%Pseudobulbus Shancigu (Shan Ci Gu).

In some embodiments, the formulation further comprises at least oneadditional herb that clears heat and fire, said herb being selected fromRhizoma, Phragmitis Communis (Lu Gen), Gardeniae Jasminoidis Fructus(Zhi Zi), Anemarrhenae Asphodeloidis Rhizoma (Zi Mu), NelumbinisNuciferae Semen (Lian Xin) and Herba Lophatheri Gracilis (Dan Zhu Ye).

In some embodiments, the at least one herb that clears heat and fire ispresent in the formulation in the following amounts: about 1-30%Rhizoma, Phragmitis Communis (Lu Gen), about 1-30% Gardeniae JasminoidisFructus (Zhi Zi), about 1-30% Anemarrhenae Asphodeloidis Rhizoma (ZiMu), about 1-30% Nelumbinis Nuciferae Semen (Lian Xin) and about 1-30%Herba Lophatheri Gracilis (Dan Zhu Ye).

In some further embodiments, the formulation further comprises at leastone astringent herb selected from Corni Officinalis Fructus (Shan ZhuYu), Semen Nelumbinis Nuciferae (Lian Zi), Pruni Mume Fructus (Wu Mai),Myristicae Fragrantis Semen (Rou Dou Kou), Fructus Terminaliae Chebulae(He Zi) and Schizandra Chinensis (Wu Wei Zi).

In such embodiments, the at least one astringent herb is present in theformulation in the following amounts: about 1-30% Corni OfficinalisFructus (Shan Zhu Yu), about 1-30% Semen Nelumbinis Nuciferae (Lian Zi),about 1-30% Pruni Mume Fructus (Wu Mai), about 1-30% MyristicaeFragrantis Semen (Rou Dou Kou), about 1-30% Fructus, TerminaliaeChebulae (He Zi) and about 1-30% Schizandra Chinensis (Wu Wei Zi).

In some further embodiments, the formulation of the invention comprisesor consists the combination of herbs listed in any of Tables 1 to 9, thecombination being in the wt % indicated or at any other wt %.

In further embodiments, the formulation of the invention is anyformulation comprising a combination of at least 4 herbs listed in anyone of Tables 1 to 9. In further embodiments, the formulation of theinvention comprises the combination of herbs depicted in any one ofTables 1 to 9.

The herbal components of the formulations of the invention may beobtained by any one method known in the art. The formulations of theinvention are typically prepared by mixing (admixing) the herbalcomponents together in the presence or absence of a carrier, anexcipient or a diluent.

The herbal components may be obtained by cooking (the herb in its rawform including all herb parts) and than concentrating the cookedmaterial into a form of dry powder. The herbal components may also beextracted as tinctures, namely as liquid extracts which maintain thepotency of the herb over time. The tinctures may be obtained asalcoholic extracts (e.g. of leaves or other plant material) or solutionsof non-volatile substances. Generally, the alcohol is ethanol.

The herbal components may also be obtained using raw herbs and boilingthem in water as in the preparation of a decoction, namely by boiling ofdissolved plant material, which may include stems, roots, bark andrhizomes. Generally, according to the process of decoction the dissolvedplant is boiled for 8-10 minutes in water (but shorter or longer boilingperiod may also be employed depending on the type of herb and itsphysical state) and is then strained.

The herbal components may also be used as commercially available.

The herbal components may be made into a concentrated dry powder form,where the powder may be either encapsulated or non-encapsulated. Theherbs may be mixed together, wherein individual concentrated dry powdersof each herb are admixed in varying ratios. A typical protocol forproducing a concentrated dry powder of a certain herb involvesextraction of the herb by boiling in a vat. A rotary extractor having acontrolled temperature and timing may be employed in this process. Onceextraction is completed the extract is exposed to low-temperature vacuumevaporation-concentration to yield a viscous liquid. The concentratedliquid is then piped into a flow coater, e.g., a granulator, whichsprays the concentrate onto minute particles of a base material anddries them to create concentrated granules. The particles may be in apowder form of the extracted herb/s or may be particles of a naturalmaterial such as potato, cornstarch or similar materials. The granulesmay then be further treated, e.g., pressed into smooth tablets or usedas concentrated powders.

Generally, the choice of a carrier, an excipient or a diluent may bedictated to some extent by the intended dosage form of the herbalformulation, the dosing regimen, the mode of administration and factorsassociated with the intended use and the subject to be treated. Herbalformulations may contain starch or may be starch-free.

The formulation of the invention may be formulated into a variety ofsolutions, emulsions, suspensions, powders, granules, natural andsynthetic materials impregnated with the individual components of theherbal formulation, pills, capsules, tablets, cachets, pastilles,lozenges, bolus, electuary, pastes, ointments, creams, plasters,lotions, transdermal patches, suppositories and syrups.

In some embodiments, the herbal formulation of the invention isformulated for oral administration. Formulations suitable for oraladministration may be presented in discrete units such as capsules,cachets or tablets each containing a predetermined amount of the herbalformulation; as a powder or granules; as a solution, a suspension or asan emulsion. The herbal formulation may also be presented as a bolus,electuary or paste. Tablets and capsules for oral administration maycontain one or more carriers, binding agents, fillers, lubricants,disintegrants, and/or wetting agents. The tablets and capsules may becoated according to methods well known in the art.

Oral liquid preparations may, for example, be in the form of aqueous oroily suspensions, emulsions or syrups or may be presented as dryproducts, e.g., in a form of a powder or granules, for constitution withwater or another suitable liquid vehicle, such as orange juice, e.g.,immediately prior to use.

In an additional aspect of the invention, there is provided the use ofany one formulation according to the invention in therapy. Thus, alsocontemplated is the use of a formulation of the invention in a methodfor treating a disease or a disorder.

The invention also provides the use of a formulation according to theinvention in the preparation of a pharmaceutical or a neutraceuticalcomposition. As will be further elaborated hereinbelow, the compositionso prepared may be employed in the prevention (prophylaxis) and/ortreatment of cancer, as an anticancer adjuvant to conventional modes ofanticancer therapy (such as radiotherapy and chemotherapy), in improvingat least one side effect associated with the treatment or prophylaxis ofcancer, in the protection of bone marrow production of red blood cellsand a variety of other therapeutic purposes.

Thus, in another aspect, the formulations of the invention are used inthe prevention and/or treatment of cancer, as anticancer formulations oras adjuvants to conventional modes of anticancer therapy, such asradiotherapy and chemotherapy.

As used herein, “cancer” refers to any carcinoma, any sarcoma, tumorssuch as multiple myeloma, Waldenstroms' (IgM) gammopathy, and Bergers(IgA), CNS lymphoma (e.g., associated with AIDS), gonadal lymphomas andleukemias, mantle cell lymphomas, vascularized stages of leukemias (bonemarrow) and lymphomas (in the lymph nodes), and any other leukemia orlymphoma, including low grade leukemias and lymphomas), solid tumors(i.e., vascularized tumors, including angiosarcomas, Kaposi's sarcoma,mesothelioma, Ewing's Sarcoma, choriocarcinoma, ascitis tumors such asovarian cancer especially with peritoneal implants), gonadal cancers.(including ovarial and cervical), airway cancers (small cell lung, lung,and bronchial), gastrointestinal cancers (pancreatic, intestinal, colon,rectal, small intestinal, polyposis, gall duct, stomach), esophagealcancer, Barrett's esophagus cancer, oral cancer, parotid cancer,nasopharyngeal cancer, thyroid cancer, CNS cancers (glial, neuroblastomamultiforme, neuromas, meningiomas, astrocytomas, any other pediatric oradult CNS cancer), urogenital cancers (bladder, renal, adrenal,prostate), skin cancers (melanoma nodular, invasive, superficialspreading MF, squamous cell, lip) bone and connective tissue cancers(breast, bone, chondromas, leiomyomas, Wilm's tumor, retinoblastoma) andany other solid carcinoma or sarcoma of pediatric or adult patients.

In some embodiments, the cancer to be treated by the methods andformulations of the invention is selected from lung cancer, non smallcell lung (NSCL) cancer, bronchioalviolar cell lung cancer, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, gastric cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, cancer of the bladder,cancer of the kidney, renal cell carcinoma, carcinoma of the renalpelvis, mesothelioma, hepatocellular cancer, biliary cancer, chronic oracute leukemia, lymphocytic lymphomas, neoplasms of the central nervoussystem (CNS), spinal axis tumors, brain stem glioma, glioblastomamultiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas,meningiomas, squamous cell carcinomas, pituitary adenomas, includingrefractory versions of any of the above cancers, or a combination of oneor more of the above cancers.

In further embodiments, the cancer is breast cancer which is not limitedto any stage, grade, histomorphological feature, invasiveness,aggressiveness or malignancy of the affected tissue or cell aggregation.

In some embodiments, the breast cancer is stage 0 breast cancer, stage Ibreast cancer, stage II breast cancer, stage HI breast cancer, stage FVbreast cancer, grade I breast cancer, grade II breast cancer, grade IIIbreast cancer, malignant breast cancer, primary carcinomas of thebreast, and all other types of cancers, malignancies and transformationsassociated with the breast.

The invention also provides a use of a formulation of the invention inimproving at least one side effect associated with the treatment orprophylaxis of a disease or disorder such as cancer. In someembodiments, a formulation of the invention is used in the treatment orprevention of side effects associated with, e.g., chemotherapy,specifically systemically administered chemotherapy. Such side effectsmay be one or more of loss of appetite, loss of sleep, fatigue,neutropenia, reduction in daily activity, decline in overall feeling,depression, digestive dysfunction, dysgeusia, anemia, weakness, pain,and impaired daily function, nausea and vomiting and combinationsthereof.

The formulations of the invention have been demonstrated to preventand/or treat side effects associated with administered chemotherapeuticagents; the formulations of the invention neither abrogate nor attenuatethe therapeutic effect of the administered chemotherapy, therebypermitting such effective use of therapeutic dosage levels. In otherwords, the formulations of the invention when used along withtraditional chemotherapy do not bring about a reduction in theanticancer therapeutic effect imposed by the chemotherapeutic agent,thereby permitting a maximum effect at the tissue desired to be treatedwith a reduction or complete elimination of side effects which areassociated with the treatment.

The formulations of the invention may be administered in conjunctionwith the administration of chemotherapy to the patient. In someembodiments, a formulation according to the invention is administeredprior to the administration of the chemotherapy. The formulation may beadministered on a single day or on several days prior to chemotherapy.

In other embodiments, the formulation of the invention is administeredfollowing administration of the chemotherapeutic agent.

In still other embodiments, the formulation is administered prior to andsubsequent to the administration of a chemotherapeutic agent and mayoptionally take place on one or multiple days prior to and one ormultiple days subsequent to the chemotherapy.

In other embodiments administration of the formulation of the inventionstarts before the initiation of chemotherapy and continues throughoutthe duration of chemotherapy.

The administration of the formulation of the invention may be once dailyor on the day of administration or multiple times a day.

In some embodiments, the formulation is administered orally three timesa day prior to, during and/or subsequent to chemotherapy.

The side effects to be minimized or prevented may be associated with anyone or more radiotherapy or any one or more chemotherapeutic agent suchas, but not limited to, 5-FU, Altretamine, Bleomycin, Busulfan,Capecitabine, Carboplatin, Carmustine, Chlorambucil, Cisplatin,Cladribine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine,Dactinomycin, Daunorubicin, Docetaxel, Doxorubicin, Epirubicin,Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxycarbamide,Idarubicin, Ifosfamide, Irinotecan, Liposomal doxorubicin, Leucovorin,Lomustine, Melphalan, Mercaptopurine, Mesna, Methotrexate, Mitomycin,Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Pentostatin,Procarbazine, Raltitrexed, Streptozocin, Tegafur-uracil, Temozolomide,Thiotepa, Tioguanine/Thioguanine, Topotecan, Treosulfan, Vinblastine,Vincristine, Vindesine, Vinorelbine, Bleomycin, Busulfan, Capecitabine,Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine,Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin,Daunorubicin, Docetaxel, Doxorubicin, Epirubicin, Etoposide,Fludarabine, Fluorouracil, Gemcitabine, Hydroxycarbamide, Idarubicin,Ifosfamide, Irinotecan, Liposomal doxorubicin, Leucovorin, Lomustine,Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone,Oxaliplatin, Paclitaxel, Pemetrexed, Pentostatin, Procarbazine,Raltitrexed, Streptozocin, Tegafur-uracil, Temozolomide, Thiotepa,Tioguanine-Thioguanine, Topotecan, Treosulfan, Vinblastine, Vincristine,Vindesine, Vinorelbine and any combination of any two or more of theseagents.

In some embodiments, the chemotherapeutic agent is selected from acombination of doxorubicin, cyclophosphamide and paclitaxel and acombination of doxorubicin, cyclophosphamide and 5-fluorouracil.

In other embodiments, the chemotherapeutic agent is a combination ofdoxorubicin, cyclophosphamide and 5-fluorouracil.

In further embodiments, the chemotherapeutic agent is a combination ofdoxorubicin, cyclophosphamide and paclitaxel.

In still further embodiments, said chemotherapeutic agent is acombination of doxorubicin, cyclophosphamide and docetaxel.

In still yet further embodiments, where the chemotherapeutic agent isadministered in conjunction with a hormonal treatment (for exampletamoxifen) and/or biological treatment (such as Herceptin), theformulation of the invention may be administered in consideration of thehormonal or biological treatment, similarly to the defined above withreference to administration methods and regimen, or independentlythereof.

Without wishing to be bound by theory, the administration of aformulation according to the invention, as disclosed, brings about thereduction in the severity of post-chemotherapy side effects andincreases the quality of life experienced by patients receivingchemotherapy. However, it is not only the side effect which contributesto the overall ill state of the subject being treated, it is also theinjury caused by such therapy to normal tissues. In fact, the successfuluse of chemotherapeutic agents to treat cancer depends upon thedifferential killing effect of the chemotherapeutic agent on cancercells compared to its effect on normal tissues.

One considerable effect is on the killing of cells associated with themanufacture of red blood cells. Acute and chronic bone marrow toxicitiesare a major limiting factor in the treatment of cancer. The formulationsof the invention have been shown to be protective of bone marrowproduction of red blood cells.

Thus, the formulations of the invention are also provided for thetreatment of a disorder associated with a deficient red blood cellproduction. The invention also provides formulations for the protectionof bone marrow production of red blood cells during and/or postchemotherapy or radiotherapy.

The disorder associated with a deficient red blood cell production maybe selected, in a non-limiting fashion, from autoimmune diseases or amalignancies, beta-thalassemia, cystic fibrosis, early anemia ofprematurity, anemia associated with chronic inflammatory disease, spinalcord injuries, acute blood loss, aging and neoplastic disease states.

In some embodiments, the deficiency in the production of red blood cellsis associated with chemotherapy.

The invention thus provides, in another one of its aspects, a method forimproving the well being or quality of life of a subject, said methodcomprising administering to the subject an effective amount of aformulation according to the invention.

According to another aspect of the present invention there is provided amethod of preventing and/or treating a disease or disorder in a subjectsuffering or having predisposition to suffering therefrom, the methodcomprising administering to the subject a therapeutically effectiveamount of a herbal formulation according to the invention.

In some embodiments, said disease or disorder is cancer, as definedabove. In some embodiments, said cancer is breast cancer. In furtherembodiments, said cancer is breast cancer.

In some embodiments, the subject suffering from said disease or disorderis a mammal, including human (males and/or females) and non-humansubjects. In some embodiments, the subject is a female subject. In otherembodiments, the subject is a male subject. In some embodiments, wherethe disease is breast cancer, the subject is a female subject.

The invention further provides a method for preventing or minimizing atleast one side effect associated with chemotherapy, the methodcomprising administering a therapeutically effective amount of at leastone formulation according to the invention to a subject prior to,subsequent to or simultaneous with the administration of chemotherapy.

The invention also provides a method for the protection of bone marrowin the course of anti-cancer treatment by chemotherapy, the methodcomprising administering a therapeutically effective amount of at leastone formulation according to the invention prior to, subsequent to orsimultaneous with the administration of chemotherapy.

The term “prevention (or prophylaxis) and/or treatment”, or any lingualvariation thereof, as used herein refers to the administering of atherapeutic amount of a formulation of the present invention which iseffective to ameliorate undesired symptoms associated with a disease, toprevent the manifestation of such symptoms before they occur, to slowdown the progression of the disease, slow down the deterioration ofsymptoms, to enhance the onset of remission period, slow down theirreversible damage caused in the progressive chronic stage of thedisease, to delay the onset of said progressive stage, to lessen theseverity or cure the disease, to improve survival rate or more rapidrecovery, or to prevent the disease form occurring or a combination oftwo or more of the above.

The “effective amount” for purposes herein is determined by suchconsiderations as may be known in the art. The amount should beeffective to achieve the desired therapeutic effect as described herein,depending, inter alia, on the type and severity of the disease to betreated and the treatment regime. The effective amount is typicallydetermined in appropriately designed clinical trials (dose rangestudies) and the person versed in the art will know how to properlyconduct such trials in order to determine the effective amount. Asgenerally known, an effective amount depends on a variety of factorsincluding the affinity of the ligand to the receptor, its distributionprofile within the body, a variety of pharmacological parameters such ashalf life in the body, on undesired side effects, if any, on factorssuch as age and gender, etc.

The invention also provides in another of its aspects a kit or acommercial package comprising a premixed formulation according to theinvention and instructions for use. In other embodiments, the kitcomprises a plurality of compartments or receptacles (e.g., bottles orvials), each comprising a single or a selection of herbs, a mixing means(e.g., a mixing container and a spatula) for mixing the herbs andinstructions for use.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible sub-ranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Additionally, the phrases “ranging/ranges between” a first indicatednumber and a second indicated number and “ranging/ranges from” a firstindicated number “to” a second indicated number are used hereininterchangeably and are meant to include the first and second indicatednumbers and all fractional and integral numerals therebetween. The term“about” as used herein indicates that the first and second numbersdefining the range may in fact be 10% above or below the indicatedlimits. For example, the expression “ranging between about 1 and 30%”refers to a concentration of between 1%±10% to 30%±10% (wt % of thetotal wt of the formulation) and any concentration therebetween. Theexpression “about 1-30%” similarly refers to a concentration between1%±10% to 30%±10% (wt % of the total wt of the formulation) and anyconcentration therebetween.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carriedout in practice, embodiments will now be described, by way ofnon-limiting example only, with reference to the accompanying drawings,in which:

FIG. 1 is a bar graph presenting the analysis of quality of life of thecombined treatment according to the present embodiments.

FIG. 2 is a bar representation showing the number of studied patientsreceiving growth factor drugs to enhance white blood or red blood count.

FIG. 3 is a bar representation showing the number of studied patients inwhich a delay in chemotherapy was affected.

FIG. 4 is a bar representation demonstrating the effect of a formulationof the invention on MDA-231 cells survival.

FIG. 5 is a bar representation demonstrating the effect of a formulationof the invention on MDA-453 cells survival.

FIG. 6 is a bar representation demonstrating the effect of a formulationof the invention on T47D cells survival.

FIGS. 7A-C are light microscopy images depicting the effect of theformulation of the invention on breast cancer adenocarcinoma cell line(T47D). FIG. 7A shows an image of a control sample. FIG. 7B shows animage of cells treated with 3 mg/ml of a formulation of the invention;and FIG. 7C shows an image of cells treated with 50 mg/ml of aformulation of the invention, and

FIGS. 8A-C are flow cytometry analysis of apoptosis of T47D carcinomacell line: FIG. 8A shows analysis of a control sample; FIG. 8B shows ananalysis of cells treated with 3 mg/ml of a formulation of theinvention; and FIG. 8C shows the results of the analysis of cellstreated with 50 mg/ml of a formulation of the invention.

DETAILED DESCRIPTION OF EMBODIMENTS

The present invention, in most general terms, relates to uniquelydesigned herbal formulations and, more particularly, but notexclusively, to herbal formulations that are suitable as complementarytherapy for cancer patients.

It is to be understood that the invention is not necessarily limited inits application to the details set forth in the following description orexemplified by the Examples, as these are provided only as non-limitingexamples of the broad aspects of the invention. The invention is capableof other embodiments or of being practiced or carried out in variousways.

As demonstrated herein, the formulations of the invention have beenfound to be highly efficacious when used in combination withchemotherapy, in reducing multiple side effects induced by thechemotherapy and in shielding the production of red blood cells, whiteblood cells and neutrophils from the toxic effects of chemotherapy.

Chemotherapy-induced nausea and vomiting (CINV) is a common and seriousproblem encountered by many patients receiving anti-cancer therapy. Upto three fourths of all cancer patients experience chemotherapy-relatedemesis. CINV complicates or prevents administration of planned therapyand decreases quality of life. Although new agents, such as palonosetronand aprepitant, have improved outcomes, CINV is still a major concernfor many patients. In older studies patients receiving chemotherapyreported nausea as the most severe symptom and vomiting as the fifth.Patients who do not receive preventive therapy have a 70% to 90%incidence of delayed emesis with high-risk agents (e.g., Adriamycine andCyclophosphamide) and a 30% to 60% risk with moderate-risk agents(Taxol).

In the studies disclosed herein, on subjects being treated according tomethodologies of the invention, 90% of the patients suffered minor or novomiting at all. Minor or no nausea has been noted in a very smallnumber of patients, needing no supplementary conventional medication,except the dose in the treatment days.

Febrile neutropenia (FN) is a severe clinical outcome that justifies theuse of colony stimulating factor (CSFs) when the risk of FN isapproximately 20% and no other equally effective regimen that does notrequire CSFs is available. Current evidence indicates that primaryprophylaxis with a CSF results in a relative risk reduction of FN byapproximately 50%. Significant reductions in documented infections havealso been demonstrated. An analysis of five trials that have reportedinfection-related mortality failed to find a significant reduction withCSF support [summary odds ratio, 0.60 (0.30, 1.22); P=0.16]. However,the power of the combined analysis was insufficient to determine thisoutcome. An additional outcome demonstrated in these trials was themaintenance of dose intensity of the chemotherapeutic regimen throughavoidance of dose reduction or delay secondary to neutropenia. The studyreported significant reductions in the risk of FN from 37% to 20% (14studies, n=3,091, relative risk reduction 46%, P<0.0001) and the risk ofinfection-related mortality from 3.3% to 1.7% (10 studies, n=2,468,relative risk reduction 48%, P=0.01).

In studies described herein, employing methodologies of the invention,80% of the patients treated with a formulation of the invention did notneed to take growth factor drugs to enhance white blood or red bloodcount. In the majority of the cases blood production was maintainedsubstantially stable throughout the chemotherapy.

Cancer treatments may interfere with the patient's ability to taste,ingest, swallow or digest food. Drugs may cause nausea, diarrhea, andanorexia. Although many new agents have been developed to combat theseside effects, patients still suffer greatly during treatment. One of themajor side effects presenting a significant challenge to the cancerpatient is alteration of taste, or dysgeusia.

Chemotherapeutic drugs are secreted or excreted in tears, saliva, sweat,bile, or urine. Drugs in the saliva may markedly alter taste(dysgeusia), leading to food revulsion and avoidance. After earlysatiety, dysgeusia is the most common challenge in patients onchemotherapy.

The two main types of dysgeusia are loss of taste acuity and distortionof taste. Loss of taste acuity comes from drug inhibition of a tastereceptor function. Taste distortion results from drugs activating thetaste receptor in an abnormally persistent fashion or preventingactivation of the receptor

The treatment of dysgeusia is typically very difficult. Treatment withagents such as zinc, folic acid, α-lipoic acid, and vitamins of the “B”class may alleviate some of the metallic taste but are only mildlyhelpful. Zinc seems to work best with a “sweet” dysgeusia. Drugs such asantracyclines and taxanes may have the worst associated dysgeusia. Theseseem to be secreted in the saliva and after the first bite or chew oftenproduce a horrible taste sensation. After drug cessation, the tastereturns to normal over a period of 2 months.

In studies described herein, employing methodologies of the invention,85% of patients reported no or minor decrease in appetite and no patientreported a digestive dysfunction or dysgeusia.

Fatigue was reported in 20% of 430 assessable patients receivingadjuvant chemotherapy (202 standard-doses, 228 high-doses) with at leasta 3-year follow-up, without change over time or difference betweentreatment arms. Mean Hb levels were lower following high-dosechemotherapy. Only 5% of patients experienced fatigue and anemia. Mentalhealth score was the strongest fatigue predictor at all assessmentmoments. Menopausal status had no effect on fatigue. Linear mixed effectmodels showed that the higher the Hb level (P=0.0006) and mental healthscore (P<0.0001), the less fatigue was experienced. Joint (P<0.0001) andmuscle pain (P=0.0283) were associated with more fatigue.

In conclusion of this study, within the patients being treated with aformulation of the invention, no patient reported severe fatigue.

In conclusion, the results demonstrate that the herbal formulationtreatment according to the present invention is safe and serves as aneffective adjunctive therapy to ameliorate multiple side effects ofchemotherapy and to enhance the immune system in cancer patients.

An exemplary formula comprises the following herbal powder extracts:Astragalus Membranaceus (Huang Qi), Poriae Cocos (Fu Ling), AtractylodesMacrocephala (Bai zhu), Lycium Chinense (Gou Qi Zi), Ligustrum Lucidum(Niu Zhen Zhi), Paeonia Lactiflora (Bai Shao), Paeonia Obovata (ChiShao), Citrus Reticulata (Chen Pi), Ophiopogon Japonicus (Mai men Dong),Milletia Reticulata (Ji Xue Teng), Oldenlandia Diffusa (Bai Hua She Shecao), Scutellaria Barbata (Ban Zhi Lian), Prunella Vulgaris (Xia KuCao), Glehnia Littoralis (Bei Sha Shen), as described herein.

Additional herbs that can be added into the formula include, forexample, Radix Pseudostellariae Heterophyllae (Tai Zhi Shen), RadixGlycyrrhizae (Gan Cao), Massa Fermentata (Shen Qu) and Fructus HordeiGerminatus (Mai Ya).

Reference is now made to the following examples, which together with theabove description illustrate some embodiments of the invention in a nonlimiting fashion.

Formulations of the Invention:

The herbs used were encapsulated dried herbal extract powders. Theherbal formula was prescribed in the dosage of 6 grams (2 grams×3 timesa day).

The extracted herbal powders where imported under license in accordancewith the regulations of the Israel Ministry of Health by “ZEN” HerbCompany (Tel Aviv, Israel) and manufactured under GMP conditions. Theplacebo capsules where provided by the same company resembling the CHTcapsules in taste, texture and appearance.

A variety of formulations have been prepared and used. The following isa description of a group of formulations prepared according to theinvention.

TABLE 1 Formulation 1. Latin name Chinese name grms Wt % 1 AstragalusMembranaceus Huang QI 10 8.1 2 Poriae Cocos Fu Ling 6 4.9 3 AtractylodesMacrocephala Bai zhu 6 4.9 4 Lycium Chinense Gou Qi Zi 8 6.5 5 LigustrumLucidum Niu Zhen Zhi 10 8.1 6 Paeonia Lactiflora Bai Shao 8 6.5 7Paeonia Obovata Chi Shao 6 4.9 8 Glehnia Littoralis Bei Sha Shen 8 6.5 9Citrus Reticulata Chen Pi 6 4.9 10 Ophiopogon Japonicus Mai men Dong 86.5 11 Milletia Reticulata Ji Xue Teng 10 8.1 12 Oldenlandia Diffusa BaiHua She She cao 15 12.2 13 Scutellaria Barbata Ban Zhi Lian 12 9.8 14Prunella Vulgaris Xia Ku Cao 10 8.1

As regards the formulations of the invention, additional herbs were usedfor particular individual symptoms; these include one or more of thefollowing exemplary herbs: Radix Pseudostellariae Heterophyllae (Tai ZhiShen), Radix Glycyrrhizae (Gan Cao), Massa Fermentata (Shen Qu) andFructus Hordei Germinatus (Mai Ya), utilized in case of digestivedisorders. Any other herb mentioned herein with reference to any oneparticular formulation may also be added to a formulation not indicatedto comprise same.

TABLE 2 Formulation 2. Latin name Chinese name Grms Wt % 1 AstragalusMembranaceus Huang Qi 20 12.4 2 Atractylodes Macrocephala Bai zhu 10 6.23 Redix Glycyrrhizae Uralensis Gan Cao 4 2.5 4 Poriae Cocos Fu Ling 85.0 5 Lycium Chinense Gou Qi Zi 12 7.5 6 Radix Paeoniae Lactiflorae BaiShao 10 6.2 7 Paeonia Obovata Chi Shao 8 5.0 8 Curcumae, Tuber Yu Jin 106.2 9 Citrus Reticulata Chen Pi 6 3.7 10 Ligustrum Lucidum Niu Zhen Zhi15 9.3 11 Oldenlandia Diffusa Bai Hua She She cao 15 9.3 12 ScutellariaBarbata Ban Zhi Lian 20 12.4 13 Prunella Vulgaris Xia Ku Cao 15 9.3 14Anemarrhenae Asphodeloidis Zi Mu 8 5.0 Rhizoma

TABLE 3 Formulation 3. Latin name Chinese name Grms Wt % 1 AtractylodesMacrocephala Bai zhu 10 5.8 2 Pseudostellaiae Heterophillae Tai Zi Shen15 8.7 3 Poriae Cocos Fu Ling 12 7.0 4 Radix Paeoniae Lactiflorae BaiShao 12 7.0 5 Radix Angelica Sinensis Dang Gui 15 8.7 6 Paeonia ObovataChi Shao 8 4.7 7 Radix Et Caulis Jixueteng Ji Xue Tang 12 7.0 8 CyperiRotundi Rhizoma Xiang Fu 8 4.7 9 Ligustrum Lucidum Niu Zhen Zhi 10 5.810 Ophiopogon Japonicus Mai men Dong 10 5.8 11 Scutellaria Barbata BanZhi Lian 20 11.6 12 Radix Isatidis Seu Baphicacanthi Ban Lan Gen 15 8.713 Prunella Vulgaris Xia Ku Cao 15 8.7 14 Anemarrhenae Asphodeloidis ZiMu 10 5.8 Rhizoma

TABLE 4 Formulation 4. Latin name Chinese name Grms Wt % 1 AtractylodesMacrocephala Bai zhu 8 4.7 2 Ginseng Radix Ren Shen 20 11.8 3 PoriaeCocos Fu Ling 10 5.9 4 Lycium Chinense Gou Qi Zi 12 7.1 5 Radix AngelicaSinensis Dang Gui 15 8.9 6 Paeonia Obovata Chi Shao 8 4.7 7 RadixSalviae Miltiorrhizae Dan Shen 12 7.1 8 Radix Et Caulis Jixueteng Ji XueTang 10 5.9 9 Citrus Reticulata Chen Pi 6 3.6 10 Glehnia Littoralis BeiSha Shen 8 4.7 11 Panacis Quinquefolii, Radix Xi Yang Shen 10 5.9 12Flos Lonicerae Japonicae Jin Yin Hua 12 7.1 13 Pseudobulbus ShanciguShan Ci Gu 18 10.7 14 Prunella Vulgaris Xia Ku Cao 20 11.8

TABLE 5 Formulation 5. Latin name Chinese name Grms Wt % 1 AtractylodesMacrocephala Bai zhu 6 3.5 2 Radix Codonopsitis Pilosulae Dang Shen 126.9 3 Poriae Cocos Fu Ling 6 3.5 4 Lycium Chinense Gou Qi Zi 15 8.7 5Radix Paeoniae Lactiflorae Bai Shao 12 6.9 6 Radix Salviae MiltiorrhizaeDan Shen 10 5.8 7 Radix Et Caulis Jixueteng Ji Xue Tang 15 8.7 8Curcumae Tuber Yu Jin 18 10.4 9 Curcuma Zedoaria E-Zhu 15 8.7 10Aucklandiae Lappae Radix Mu Xiang 12 6.9 11 Ligustrum Lucidum Niu ZhenZhi 12 6.9 12 Smilacis Glabrae, Rhizoma Tu Fu Ling 15 8.7 13Pseudobulbus Shancigu Shan Ci Gu 15 8.7 14 Anemarrhenae Asphodeloidis ZiMu 10 5.8 Rhizoma

TABLE 6 Formulation 6. Latin name Chinese name Grms Wt % 1 AstragalusMembranaceus Huang Qi 20 11.2 2 Atractylodes Macrocephala Bai zhu 12 6.73 Poriae Cocos Fu Ling 8 4.5 4 Radix Angelica Sinensis Dang Gui 12 6.7 5Radix Salviae Miltiorrhizae Dan Shen 10 5.6 6 Radix Et Caulis JixuetengJi Xue Tang 10 5.6 7 Curcumae Tuber Yu Jin 12 6.7 8 Aucklandiae LappaeRadix Mu Xiang 8 4.5 9 Sangjisheng, Ramulus Sang Zi Sheng 10 5.6 10Panacis Quinquefolii, Radix Xi Yang Shen 15 8.4 11 Radix Isatidis SeuBan Lan Gen 18 10.1 Baphicacanthi 12 Flos Lonicerae Japonicae Jin YinHua 15 8.4 13 Prunella Vulgaris Xia Ku Cao 20 11.2 14 AnemarrhenaeAsphodeloidis Zi Mu 8 4.5 Rhizoma

TABLE 7 Formulation 7. Latin name Chinese name Grms Wt % 1Pseudostellaiae Heterophillae Tai Zi Shen 15 8.5 2 Herba LobeliaeChinensis Cum Ban Bian Lian 10 5.7 Radice 3 Rhizoma Alismatis Ze Xie 84.5 4 Rhemanniae Glutinosae Shu Di Huang 12 6.8 Conquitae Radix 5Persicae Semen Tao Ren 12 6.8 6 Curcuma Zedoaria E-Zhu 15 8.5 7 DiospyriKaki Calyx Xi Di 8 4.5 8 Radix Adenophorae Seu Sha Shen 12 6.8 Glehniae9 Sophorae Subprostratae Radix Shan Dou Gen 15 8.5 10 PseudobulbusShancigu Shan Ci Gu 12 6.8 11 Rhizoma, Phragmitis Communis Lu Gen 15 8.512 Gardeniae Jasminoidis Fructus Zhi Zi 12 6.8 13 Nelumbinis NuciferaeSemen Lian Xin 12 6.8 14 Herba Lophatheri Gracilis Dan Zhu Ye 18 10.2

TABLE 8 Formulation 8. Latin name Chinese name Grms Wt % 1 RadixCodonopsitis Pilosulae Dang Shen 12 6.9 2 Pseudostellaiae HeterophillaeTai Zi Shen 15 8.6 3 Coicis Lachryma-jobi Semen Yi Yi Ren 12 6.9 4 SemenPlantaginis Che Qian Zi 10 5.7 5 Arilus Euphoriae Longanae Long Yang Rao8 4.6 6 Mori Albae Fructus Sang Shen 18 10.3 7 Paeonia Obovata Chi Shao8 4.6 8 Persicae Semen Tao Ren 6 3.4 9 Cyperi Rotundi Rhizoma Xiang Fu 84.6 10 Plastrum, Testudinis Gui Ban 15 8.6 11 Panacis Quinquefolii,Radix Xi Yang Shen 15 8.6 12 Taraxaci Mongolici Cum Pu Gong Yin 18 10.3Radice Herba 13 Sophorae Subprostratae Radix Shan Dou Gen 12 6.9 14Prunella Vulgaris Xia Ku Cao 18 10.3

TABLE 9 Formulation 9. Latin name Chinese name Grms Wt % 1. RadixCodonopsitis Pilosulae Dang Shen 20 11.6 2 Herba Lobeliae Chinensis CumBan Bian Lian 12 6.9 Radice 3 Fructus Kochia S copariae Di Fu Zi 10 5.84 Mori Albae Fructus Sang Shen 10 5.8 5 Flos Carthami Tinctorii Homg Hua8 4.6 6 Persicae Semen Tao Ren 8 4.6 7 Diospyri Kaki Calyx Xi Di 12 6.98 Citri Aurantii Fructus Zhi Ke 10 5.8 9 Citri Aurantii Fructus Zhi Shi10 5.8 Immaturus 10 Plastrum, Testudinis Gui Ban 18 10.4 11 SmilacisGlabrae, Rhizoma Tu Fu Ling 20 11.6 12 Pseudobulbus Shancigu Shan Ci Gu15 8.7 13 Gardeniae Jasminoidis Fructus Zhi Z 10 5.8 14 Herba LophatheriGracilis Dan Zhu Ye 10 5.8

Study Design and Subjects:

Breast cancer patients receiving formulation 1 of the invention inconcurrent with chemotherapy, were reviewed over a period of 3 years.The patients aged 18-70, having localized tumors, exhibited Karnovskyperformance status >80% and were candidates for adjuvant or neodajuvantchemotherapies with anthracyclines-based combination with or withouttaxanes at the Sorasky Oncology department Center. All patients hadbiopsy proven disease, were chemonaive and had normal liver and kidneyfunction (up to X2 of ULN values) with initial blood count: Hb>10,WBC>3000, platelets>100,000. Thus, all patients included in this studywere treated in parallel by conventional chemotherapy in oncologydepartments at academic conventional hospitals. The content of theherbal formulation was never made known to them or made public at thetermination of the study.

Treatment Applied:

Chemotherapy applied to patients was adjuvant or neo-adjuvant standardprotocol for breast cancer treatment, which, in the majority of thetested patients, included a combination of doxorubicin (Adriamycine),cyclophosphamide (Cytophosphan) and paclitaxel (Taxol) (AC+T) ordoxorubicin (Adriamycine), cyclophosphamide (Cytophosphan) and5-fluorouracil (5-FU) (CAF). The chemotherapy was applied according to atypical and well-known international chemotherapy protocols, as follows:

1. Four treatments of Adriamycine 60 mg/m² and Cytophosphan 600 mg/m²,every 3 weeks for 4 cycles (AC protocol).

2. Four treatments of Adriamycine 60 mg/m² and Cytophosphan 600 mg/m²,every 3 weeks for 4 cycles, followed by Taxol 80 mg/m², every week for12 weeks (AC+T protocol).

3. Three cycles of Cytophosphan 500 mg/m², Adriamycine 50 mg/m² and 5-FU500 mg/m², every 3 weeks for 6 cycles (CAF protocol).

4. Dose dense AC every 2 weeks followed by paclitaxel 175 mg/m² every 2weeks, with WBC stimulants (Neupogen/Neulastim) support (dd. AC+Tprotocol).

Patients treated with one of first 2 regimens received Epirubicin 90mg/m² substituting Adriamycin at the discretion of attending physician.

Following enrollment, patients were blindly randomized to receive eithercapsules containing a formulation according to the invention (typicallyformulation 1) or placebo capsules. Capsules containing formulation 1 oran equivalent according to the invention contained an effective amountof a homogeneous mixture of herbal extract powders. The extracted herbalpowders where imported under license as described above.

Example 1

The records from 20 consecutive breast cancer patients, having beentreated with formulation 1 of the invention or an equivalent thereof, inparallel with conventional therapy, were analyzed for the study. Table10 lists the baseline characteristics of these patients.

TABLE 10 Baseline data on patients receiving adjuvant treatment inconjunction with chemotherapy. Values are numbers (percentages) ofparticipants unless otherwise indicated. Baseline Data Patients Number20 Mean age, years (SD) 52.64 (±2.08) Body weight 65.47 (±3.75) BRCA 1/24 (20%) Cancer + Stage IDC grade 2-3 16 (80%) ILC 2 (10%) DCIS 1 (5%)Metastatic cancer 1 (5%) Treatment protocols AC 5 (25%) AC + T 7 (35%)CAF 5 (25%) Other* 3 (15%) *Other protocols included: CEF + taxotere,CEF + taxol.

Analysis of post-treatment scores, presented in FIG. 1, showed lowscores of chemotherapy side-effects in the categories of vomiting(Avg=0.9), nausea (Avg=1.15), appetite (Avg=1.3), weakness (Avg=1.25),pain (Avg=0.7), bowel function (Avg=0.75), fatigue (Avg=1.3) andimpaired daily function (Avg=1.25). As presented in FIG. 1, the majorityof the patients treated with formulation 1 of the invention demonstratedreduced incidence of the various side effects.

Since low scores of white blood cells (WBC), in particular, butsometimes also of red blood cells (RBC) is a common side effect ofchemotherapy to breast cancer patients, the need for using growth factordrugs to enhance white blood or red blood count was also evaluated. Asdepicted in FIG. 2, the majority of patients did not require treatmentwith growth factor drugs; therefore, attesting to the ability of theformulation of the invention to effect maintenance and protection ofblood cells production.

The delay in chemotherapy treatment according to the clinical benefitquestionnaires was also tested as means to understanding the effect ofthe formulation of the invention on the overall ability of a patient toundergo chemotherapy while being treated with a formulation of theinvention. As shown in FIG. 3, out of 20 patients, only 3 patientsreported delay in one treatment and one patient reported delay in twotreatments. The majority of the patients were able to sustain thescheduled regimen and drug doses when treated also with the formulationof the invention, thereby increasing success for treatment.

Importantly, no herbal-related adverse effects were reported at anytime.

The results of this study demonstrated that the use of the formulationsdescribed herein was effective in alleviating side effects of breastcancer patients receiving chemotherapy.

In summary, the formulations of the invention have been shown to act asadjunctive treatment to ameliorate multiple side effects ofchemotherapy, as follows:

Vomiting and nausea: It is shown (FIG. 1) that 90% of the patients hadminor or no vomiting at all. Minor or no nausea has been noted in veryfew patients, without any need for supplementary conventional medication(in addition to the applied chemotherapy).

Febrile neutropenia (FN): There have been no reports of FN during thestudy.

Use of growth factor drugs: Only four patients (20%) reported the needto take growth factor drugs to enhance white blood or red blood count.

Alteration of taste (dysgeusia): In this study, 85% of patients reportedno or minor decrease in appetite and no patient reported any significantdigestive dysfunction or dysgeusia.

Fatigue: The results demonstrate that none of the patients receiving theformulation of the invention reported severe fatigue.

This study demonstrates that herbal formulation treatments according tothe invention are safe and may serve as an effective adjunctive therapyto ameliorate multiple side effects of chemotherapy and to enhance theimmune system in cancer patients.

Example 2

This study aimed at assessing the efficacy, tolerability and sideeffects of the formulation of the invention as a complement toneoadjuvant and adjuvant chemotherapy treatment of breast cancerpatients. The study shed light on the clinical importance andimplications of the unique formulation of the invention describedherein, as adjunctive treatment for ameliorating multiple side effectsof chemotherapy in breast cancer treatment.

Study methodology: The clinical study is a unicenter, randomized,double-blind placebo controlled clinical trial.

Population: Breast cancer patients receiving neoadjuvant and adjuvanttreatment of Tel Aviv Medical Center Oncology Department.

Patients were treated for a minimum of 20 weeks, starting 2 weeks priorto chemotherapy, clinically evaluated every 6 weeks, up to 1 month postchemotherapy.

The follow-up was according to the usual protocol in neoadjuvant andadjuvant chemotherapy.

Imaging methods: Patients entering the trial were evaluated by imagingmethods according to conventional protocol, as other patients treatedwith neoadjuvant and adjuvant chemotherapy. Patients receivingneoadjuvant chemotherapy in the trial had core biopsy histologicallyproven breast cancer. Clinical or sonographic suspicious auxiliary lymphnodes were further evaluated by FNA or core biopsy. For patientsreceiving neoadjuvant chemotherapy, metallic markers were introducedwith ultrasonographic guidance, during the chemotherapeutic treatment.Post surgery patients were evaluated only by their pathological resultsfrom the tumor removed. The following methodologies were employed in thecourse of evaluation:

-   -   1. Mammography: Standard two views examinations of both breasts        complemented by 90° lateral view and magnifications views.    -   2. Whole breast ultrasound with evaluation of the axillas.    -   3. Breast MRI of both breasts or PET-CT. Potentially more        accurate of both previous methods in evaluation of the disease        extension and in the evaluation of the contralateral breast for        occult disease by other methods.

Chemotherapy: Neoadjuvant, adjuvant and treatment standardchemotherapeutic protocols for breast cancer.

Chemotherapy was administered according to standard adjuvant orneoadjuvant protocols for breast cancer treatment. Most of the patientsreceived a combination of doxorubicin (Adriamycin), cyclophosphamide(Cytophosphan) and paclitaxel (Taxol) (AC+T) or doxorubicin(Adriamycin), cyclophosphamide (Cytophosphan) and 5-fluorouracil (5FU)(CAF), according to accepted international chemotherapy protocols.

Herbal treatment: Formulation 1 of the invention. Each of the herbalcomponents was in the form of an encapsulated dried herbal extractpowder imported by the “ZEN” Herb Company and manufactured under GMPconditions.

Patients were divided into two groups:

Group A: received formulation 1 in a dosage of 6 grams (2×3 grams) perday.

Group B: received placebo, resembling the herbal capsules in taste,texture and appearance, and consisting of flavored bred crams.

Visit 1: 2 weeks prior to chemotherapy—

Patients meeting inclusion criteria received an information sheet,signed informed consent form and then evaluated by an oncologist andgiven the herbal formula. Next, patients were randomly divided into the2 groups A and B, as above (a formulation group and a placebo group).

Randomization was made in a manner that each group consisted of asimilar number of patients of each malignancy.

Visits 2-8: every 3 weeks (according to neo-adjuvant or adjuvantchemotherapy standard protocol)—

Visits included oncologist evaluation and physical examination accordingto standard protocol.

Patients in the research were handled in a double blind-fashion. Eachpatient received a sealed container with a 21-day supply of pills,containing 315 pills: calculated as 5 pills 3 times a day for 21 days.During each follow up visit the patients received the next dosage.Instructions were to take the 5 capsules 30 min before meals, 3 times aday.

Treatment was started 2 weeks prior to the first dose of chemotherapyand lasted to the last day of chemotherapy. Patients were seen byattending physicians at least every 6 weeks and had blood counts beforeeach chemotherapy dose or when admitted for complication.

Table 11 summarizes the demographic data for the study group whichconsisted of 65 breast cancer female patients with localized tumors.Thirty-four were randomized to receive formulation 1 and thirty-one toreceive placebo. The median age was 52 years (range 24-68), about athird of the patients were treated in the neoadjuvant setting while therest received adjuvant therapy. The use of dose-dense and taxane-basedregimens was equally distributed among the study groups. Two patients ineach group did not start the allocated protocol. Full compliance withtreatment arm was assigned to 24 of 34 women allocated to formulation 1and to 17 of those assigned to placebo.

TABLE 11 Clinical and demographic characteristics at baseline.Formulation 1 Placebo P-value No of patients 34 31 Age median 47.5852.16 range 24-67 28-68 Histology 0.32 Invasive Ductal (IDC) 20 24Invasive Locular (ILC) 2 2 IDC + ILC 11 5 Other 1 Hormone receptors: ER,PR Negative 8 5 0.46 positive 26 26 Her-2 Negative 26 19 0.11Intermediate 5 3 Positive 3 3 9 Protocol Compliance 0.39 Full compliance24 17 Partial compliance 8 12 Not started 2 2

Hematological toxicities associated with anemia (hemoglobinconcentration of less than 10 gram %) and neutropenia and leucopenia(total WBC<3.0×10⁹/L or absolute neutrophile (ANC) count <1000×10⁹/L)were significantly reduced in patients treated with the formulation ofthe invention (Table 12). In sub-group analysis according tochemotherapy schedules, the protective effect against anemia was noticedonly in groups receiving Adriamycin and Cytoxan every 3 weeks(hemoglobin concentration of less than 10 gram in 4% of patients treatedwith the formulation of the invention and 50% of placebo patients,p=0.003), while the protective effect against neutropenia was noticedonly in the dose-dense group (ANC<1.5×10⁹/L in 33% of placebo patientsand 0% of groups treated with the formulation of the invention,respectively). Neutropenic fever episodes occurred in 2 and 4 patientsof the formulation-treated and placebo groups, respectively,non-significant difference (p=0.32). Sever infections occurred in 3patients in the placebo group and none in the group treated with theformulation, non-significant difference (p=0.10)).

TABLE 12 Hematological Toxicity by treatment group Grade 1 and Abovegrade 1 under (%) (Grade 2-4) (%) P value Anemia <10.0 g/dl >10.0 g/dlCHM  >28(82%)   6(18%) 0.0081 Placebo 16(52) 15(48) Leukopenia <3.0 ×10⁹/L >3.0 CHM 28(82)  6(18) 0.0315 Placebo 18(58) 13(42) neutropenia<1.5 × 10⁹/L >1.5 CHM 25(73)  9(27) 0.063 Placebo 16(52) 15(48)Thrombocytopenia <75.0 × 10⁹/L  >75.0 CHM  34(100) 0  0.258 Placebo28(3)  2(7) Lymphopenia <0.8 >0.8 CHM 23(68) 11(32) 0.2139 Placebo16(51) 15(49) Grade 2 and Above Grade 2 under (%) (%) P value Leukopenia<2.0 × 10⁹/L >2.0 CHM 33(97) 1(3) 0.0475 Placebo 18(58) 13(42)neutropenia <1.0 × 10⁹/L >1.0 CHM 30(88)  4(12) 0.0447 Placebo 21 (52)10(32) Lymphopenia <0.5 × 10⁹/L >0.5 CHM 31(91) 3(9) 1.0 Placebo 28(90) 3(10)

Example 3 Cell Culture and Reagents

The human Breast cell lines, MDA-231 and MDA-453, were obtained from theAmerican Type Culture Collection (ATCC). Both cell lines were grown andmaintained in Dulbecco's modified Eagle's medium (DMEM, BiologicalIndustries, Beit HaEmek, Israel) supplemented with 10% fetal calf serum(FCS), 1% penicillin and 1% streptomycin (full medium) at 37° C., in anatmosphere of 95% oxygen and 5% CO₂.

The herb formulation is the formulation of the invention as describedherein.

Cell Viability Assay:

Cells (2-5×10³/well) were seeded in 96-well plastic plates and incubatedat 37° C. in full medium containing the tested formulation. After 48 and72 hours, cell viability was assessed by the ability of metabolicallyactive cells to reduce tetrazolium salt (XTT) to colored formazancompounds. The absorbance of the samples was measured with an ELISAreader (wavelength 450 nm, reference wavelength 630 nm). Eachmeasurement was performed in triplicate. The data are mean values fromthree different experiments.

The treatment was started after 24 h of cell culturing in order todetermine the effect of the formulation of the invention on cellsurvival. This effect was calculated by comparing the density of theintact cells to the density of the treated cells. Cell density wasdetermined by the XTT assay as follows. Cells (2-5×10³/well) were seededin 96-well plastic plates and incubated at 37° C. in full mediumcontaining the test drugs. The formulation of the invention was added invarying concentrations (1-100 mg/ml) to each of three replicate wellsand incubated for 72 h. A freshly prepared mixture of XTT and anactivation reagent (PMS) was added to each well (50 μl). Following 2 hof incubation at 37° C., the plates were placed on a mechanical plateshaker of a computerized automatic micro-well plate spectrophotometerand shaken for 30 sec and the optical densities (ODs) of the dye wereread at 450 nm. The measurements were repeated following 4 and 6 h ofincubation. The time point of the assay at which there were optimal ODreadings was chosen to count the cell number. When more than one timepoint fitted this criterion, the results for the different time pointswere normalized and averaged. The OD readings were previously shown tocorrelate well (r>0.97-0.99) with the number of cells/well.

Light Microscopy.

T47D breast adenocarcinoma cells were plated at a density of 5×10⁶ per10-cm dish with different concentrations of the herbal formulation ofthe invention and after 24 h visualized by light microscopy ×200.

Flow Cytometry Analysis.

T47D cells were plated at a density of 5×10⁶ per 10-cm dish with thetest drugs at selected concentrations. The adherent and non-adherentcells were collected during exponential growth of the cells and counted.A total of 1-2×10⁶ cells were washed in phosphate-buffered saline (PBS)and the pellet was fixed in 3 ml ethanol for 1 h at 4° C. Before theanalysis, the cells were pelleted and resuspended in 1 ml PBS andincubated for 30 min with 0.64 mg/ml RNAse at 37° C. They were stainedwith 45 propidium iodide (PI) for at least 1 h before analysis by flowcytometry. Data acquisition was performed on a FACScan and analyzed byCellQuest software (Becton Dickinson Immunocytometry Systems, San Jose,Calif., USA). All fluorescence and laser light scatter measurements weremade with linear signal processing electronics. Data for at least 15,000cells were collected for each data file. A standard protocol for cellcycle distribution and cell size was used. Necrotic cells were excludedby counting cells following staining with trypan blue before fixation.All experiments were done three times.

Statistical Analysis.

The results were calculated as mean±SE. The difference between theintact and treated cells was evaluated by the one-way Student's T-testusing an SPSS software package (SPSS Inc., Chicago, Ill., USA).Significance (p<0.05) was established by the post hoc Tukey's pairwisecomparison.

Effect of the Formulation of the Invention on Cell Survival.

A dose-dependent inhibitory effect of the formulation of the inventionon cells survival was found in MDA-231, MDA-453 and T47D human breastcarcinoma cell lines (FIGS. 4, 5 and 6, respectively). IC50 wasapproximately similar (25 mg/ml) on all 3 carcinoma cell lines tested.

Assays were also conducted with breast cancer adenocarcinoma cells(T47D). The results are presented in FIGS. 7A-C. As demonstrated,administration of the formula of the invention causes cell death ofcancer cells and does not only reduce side effects associated with thetreatment, thereby making chemotherapy treatments more effective andalso having additional effect in reducing the recurrence of the treateddisease.

Induction of Apoptosis.

The extent of apoptosis was assessed by flow cytometry analysisfollowing 72 h of exposure of the cells to the different concentrationsof the formulation of the invention. The formulation of the inventionincreased the percentage of cells with sub-diploid DNA content, thehallmark of apoptosis, in a dose-dependent manner in the T47D carcinomacell line (FIGS. 8A-C).

1.-70. (canceled)
 71. A method for treating bladder cancer or preventingrecurrence of bladder cancer, the method comprising administering asubject in need thereof a herbal formulation comprising a combination ofat least five herbs, each being selected from: at least one herb thattonifies the Qi; at least one herb that drains dampness; at least oneherb that tonifies blood; at least one herb that invigorates the blood;at least one herb that regulates the flow of Qi; at least one herb thattonifies yin; at least one herb that clears heat and relieves toxicity;and at least one herb that clears heat and fire; wherein the at leastone herb that tonifies the Qi is selected from the group consisting ofAstragalus Membranaceus (Huang QI), Atractylodes Macrocephala (Bai zhu),Ginseng Radix (Ren Shen), Radix Codonopsitis Pilosulae (Dang Shen),Pseudostellaiae Heterophillae(Tai Zi Shen) and Redix GlycyrrhizaeUralensis (Gan Cao); wherein the at least one herb that drains dampnessis selected from the group consisting of Poriae Cocos (Fu Ling), CoicisLachryma-jobi Semen (Yi Yi Ren), Herba Lobeliae Chinensis Cum Radice(Ban Bian Lian), Semen Plantaginis (Che Qian Zi), Fructus KochiaScopariae (Di Fu Zi) and Rhizoma Alismatis (Ze Xie); wherein the atleast one herb that tonifies blood is selected from the group consistingof Lycium Chinense (Gou Qi Zi), Radix Paeoniae Lactiflorae (Bai Shao),Radix Angelica Sinensis (Dang Gui), Arilus Euphoriae Longanae (Long YangRao), Mori Albae Fructus (Sang Shen) and Rhemanniae Glutinosae ConquitaeRadix (Shu Di Huang); wherein the at least one herb that invigorates theblood is selected from the group consisting of Paeonia Obovata (ChiShao), Radix Salviae Miltiorrhizae (Dan Shen), Radix LigusticiChuanxiong (Chuanxiong), Flos Carthami Tinctorii (Homg Hua), Radix EtCaulis Jixueteng (Ji Xue Tang), Curcumae, Tuber (Yu Jin), Persicae,Semen (Tao Ren) and Curcuma Zedoaria (E-Zhu); wherein the at least oneherb that regulates the flow of Qi is selected from the group consistingof Citrus Reticulata (Chen Pi), Aucklandiae Lappae Radix (Mu Xiang),Diospyri Kaki Calyx (Xi Di), Cyperi Rotundi Rhizoma (Xiang Fu), CitriAurantii Fructus (Zhi Ke) and Citri Aurantii Fructus Immaturus (ZhiShi); wherein the at least one herb that tonifies the yin is selectedfrom the group consisting of Ligustrum Lucidum (Niu Zhen Zhi),Ophiopogon Japonicus (Mai men Dong), Glehnia Littoralis (Bei Sha Shen),Sangjisheng, Ramulus (Sang Zi Sheng), Plastrum, Testudinis (Gui Ban),Ophiopogonis Japonici, Tuber (Mai Men Dong), Panacis Quinquefolii, Radix(Xi Yang Shen) and Radix Adenophorae Seu Glehniae (Sha Shen); whereinthe at least one herb that clears heat and relieves toxicity is selectedfrom the group consisting of Oldenlandia Diffusa (Bai Hua She She cao),Scutellaria Barbata (Ban Zhi Lian), Radix Isatidis Seu Baphicacanthi(Ban Lan Gen), Flos Lonicerae Japonicae (Jin Yin Hua), TaraxaciMongolici Cum Radice Herba (Pu Gong Yin), Sophorae Subprostratae Radix(Shan Dou Gen), Smilacis Glabrae, Rhizoma (Tu Fu Ling) and PseudobulbusShancigu (Shan Ci Gu); wherein the at least one herb that clears heatand fire is selected from the group consisting of Prunella Vulgaris (XiaKu Cao), Rhizoma, Phragmitis Communis (Lu Gen), Gardeniae JasminoidisFructus (Zhi Zi), Anemarrhenae Asphodeloidis Rhizoma (Zi Mu), NelumbinisNuciferae Semen (Lian Xin) and Herba Lophatheri Gracilis (Dan Zhu Ye).72. The method according to claim 71, wherein the formulation comprisesat least one herb that tonifies the Qi, at least one herb that drainsdampness, at least one herb that tonifies the yin, at least one herbthat clears heat and relieves toxicity and at least one herb that clearsheat and fire.
 73. The method according to claim 71, wherein theformulation comprises Poriae Cocos (Fu Ling), Radix Paeoniae Lactiflorae(Bai Shao), Ligustrum Lucidum (Niu Zhen Zhi), Ophiopogon Japonicus (Maimen Dong), Scutellaria Barbata (Ban Zhi Lian), Taraxaci Mongolici CumRadice Herba (Pu Gong Yin) and Prunella Vulgaris (Xia Ku Cao).
 74. Themethod according to claim 71, wherein the formulation comprisesAstragalus Membranaceus (Huang Qi), Poriae Cocos (Fu Ling), RadixPaeoniae Lactiflorae (Bai Shao), Ligustrum Lucidum (Niu Zhen Zhi),Ophiopogon Japonicus (Mai men Dong), Oldenlandia Diffusa (Bai Hua SheShe cao), Scutellaria Barbata (Ban Zhi Lian), Taraxaci Mongolici CumRadice Herba (Pu Gong Yin) and Prunella Vulgaris (Xia Ku Cao).
 75. Themethod according to claim 74, wherein the formulation further comprisingat least one of Glehnia Littoralis (Bei Sha Shen), Citrus Reticulata(Chen Pi), Radix Et Caulis Jixueteng (Ji Xue Tang), AtractylodesMacrocephala (Bai zhu), Paeonia Obovata (Chi Shao) and Lycium Chinense(Gou Qi Zi).
 76. The method according to claim 71, for reducingrecurrence of the treated cancer.
 77. A herbal formulation selected fromthe group consisting of a. a formulation comprising a combination ofAstragalus membranaceus, Poriae cocos, Atractylodes macrocephala,Ligustrum lucidum and Lycium chinense. b. a formulation comprisingPoriae Cocos (Fu Ling), Radix Paeoniae Lactiflorae (Bai Shao), LigustrumLucidum (Niu Zhen Zhi), Ophiopogon Japonicus (Mai men Dong), ScutellariaBarbata (Ban Zhi Lian), Taraxaci Mongolici Cum Radice Herba (Pu GongYin) and Prunella Vulgaris (Xia Ku Cao); and c. a formulation comprisingAstragalus Membranaceus (Huang Qi), Poriae Cocos (Fu Ling), RadixPaeoniae Lactiflorae (Bai Shao), Ligustrum Lucidum (Niu Zhen Zhi),Ophiopogon Japonicus (Mai men Dong), Oldenlandia Diffusa (Bai Hua SheShe cao), Scutellaria Barbata (Ban Zhi Lian), Taraxaci Mongolici CumRadice Herba (Pu Gong Yin) and Prunella Vulgaris (Xia Ku Cao).
 78. Theformulation according to claim 77, wherein formulation (c) furthercomprising at least one of Glehnia Littoralis (Bei Sha Shen), CitrusReticulata (Chen Pi), Radix Et Caulis Jixueteng (Ji Xue Tang),Atractylodes Macrocephala (Bai zhu), Paeonia Obovata (Chi Shao) andLycium Chinense (Gou Qi Zi).